Most epilepsy patients show improved health with drug therapy, but no therapeutic influences are shown on about 10 to 15% of epilepsy patients. Thus, a surgical treatment of the brain lesion responsible for the onset of seizures is very important to drug therapy-resistant patients. In this regard, an epileptic lesion must be accurately detected, which is typically carried out by imaging and quantifying benzodiazepine receptors in epileptic lesion loci.
In a normal brain, high concentrations of benzodiazepine receptors are found at the cerebral cortex, the cerebellum, and the thalamus, with a low concentration detected at the caudate nucleus. Taking advantage of the fact that the concentration of benzodiazepine receptors is reduced in an epileptic lesion, the imaging of benzodiazepine receptors can be applied to the localization of the epileptic lesion and the diagnosis of epilepsy.
There are many diagnosis methods of an epileptic lesion including magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), interictal electroencephalography, and ictal electroencephalography. Of them, MRI is the most widely used diagnosis method and can detect an epileptic lesion once the brain undergoes a syntactical change. In contrast, SPECT and PET can be applied to the detection of an epileptic lesion in the presence of even a biochemical change prior to the syntactical change, and thus have an advantage over MRI in terms of accurate diagnosis in the initial phase.
PET imaging of epileptic lesions can be understood based on the knowledge of the mechanism or biochemical change of epilepsy. The radiopharmaceutical fluorine-18-labeled fluoro-deoxyglucose ([18F]FDG) is one of the most widely used for epilepsy imaging. Being involved in glucose metabolism in the brain, the radio-labeled fluoro-deoxyglucose can be used to visualize the metabolism activity of the brain, as evaluated for cerebral glucose metabolism by PET images. Extensive studies have been done on PET imaging of epileptic lesions with fluoro-deoxyglucose, reporting that epileptic regions exhibit a low level of glucose metabolism at the interictal phase. The brain, however, fundamentally exhibits a high fluoro-deoxyglucose uptake, so that the S/N (signal-to-noise) ratio is decreased. Further, the uptake influences the outskirt of the lesion, causing the false impression that a decreased level of the glucose metabolism might be detected over a scope wider than the practical lesion. In addition, because PET images of epileptic lesions using fluoro-deoxyglucose are poor in reliability, and are greatly affected by other compounds having influence on the glucose metabolism, or by physical conditions, the use of fluoro-deoxyglucose alone is limitedly applied to the diagnosis of epilepsy.
Among positron-emitting radionuclides used for PET, carbon-11 (t1/2=20.4 min), nitrogen-13(t1/2=9.98 min), oxygen-15(t1/2=2.03 min), fluorine-18 (t1/2=109.8 min), copper-64 (t1/2=12.7 min), and iodine-124 (t1/2=4.2 days) are produced in a cyclotron, and gallium-68 (t1/2=68.03 min) in a generator. PET images obtained from carbon-1′-labeled flumazenil ([11C]flumazenil), one of the most widely used benzodiazepine receptor antagonists, provide a more accurate localization for epileptic lesions than those from other radionuclides. [11C]flumazenil is advantageous in that the benzodiazepine receptor-targeting pharmaceutical flumazenil does not undergo structural and chemical changes at all. However, the half life of 20 min of the radionuclide leaves no spare time for labeling operation and post-labeling processes. Further, [11C]flumazenil emits a large dose of radiation and can be applied to up to 2 patients only, depending on the number of PET instruments.
On the other hand, the positron-emitting radionuclide fluorine-18 has a relatively long half life (t1/2=109.8 min) and is easy to label to compounds through organic synthesis, so that it can be used in the synthesis of radiopharmaceuticals, which takes time, and the study of physiological metabolisms, which are typically slow progressing. Accordingly, preference is made for flumazenil labeled with fluorine-18 rather than fluorine-19 because it more effectively allows for the analysis of compounds for in vivo activity through real-time PET images. Thus far, the synthesis of [18H]flumazenil ([18F]FMZ) has been achieved by direct nucleophilic labeling of the nitromazenil (NO2-mazenil) precursor, but with a radiochemical yield as low as 5 to 20%, so that the quantity obtained only satisfies the need for several persons' supply of radionuclide. In order to meet the demand of clinical research, an automatic synthesis apparatus has been applied, but resulted in a yield of 1% or lower. There has not yet been reports on the mass production of [18F]flumazenil using an automatic synthesis apparatus. To overcome the problems encountered in the prior art, the flumazenil derivatives fluorine-18 fluoroethyl flumazenil ([18F]FEFMZ, (5-(2′-[18F]fluoroethyl)flumazenil)) and fluorine-18 fluoroflumazenil ([18F]FFMZ, (2′-[18F]fluoroflumazenil) have been developed, but they, different in chemical structure from flumazenil, exhibit different pharmacokinetic profiles. In addition, the fluorine-18 which is located on the aliphatic moiety is apt to undergo defluorination in vivo, resulting in low signal-to-noise ratios, and degrading the quality of flumazenil-based, benzodiazepine receptor PET images of the brain due to non-target images of fluorine-18-labeled metabolites. Hence, these radionuclides are not extensively applied to clinical research.